{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:54:18Z","timestamp":1793073258220,"version":"4.5.0"},"reference-count":14,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2003,11]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic>Background and Purpose\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response\u2013finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Methods\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (\u0394SSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Results\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean \u0394SSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on \u0394SSS in the tissue plasminogen activator\u2013treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Conclusions\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.\n                  <\/jats:p>","DOI":"10.1161\/01.str.0000092527.33910.89","type":"journal-article","created":{"date-parts":[[2003,10,20]],"date-time":"2003-10-20T20:31:20Z","timestamp":1066681880000},"page":"2543-2548","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":391,"title":["Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN)"],"prefix":"10.1161","volume":"34","author":[{"given":"Michael","family":"Krams","sequence":"first","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kennedy R.","family":"Lees","sequence":"additional","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Hacke","sequence":"additional","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Grieve","sequence":"additional","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Orgogozo","sequence":"additional","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A.","family":"Ford","sequence":"additional","affiliation":[{"name":"From Pfizer Global Research and Development, Sandwich, UK (M.K., A.P.G.); University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK (K.R.L.); Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany (W.H.); CHU Pellegrin, Bordeaux, France (J-M.O.); and Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle, UK (G.A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-200106000-00014"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.9.10.2281"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2001.7835"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.57.8.1428"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1185\/030079902125000688"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)01503-5"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000077016.55891.2e"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000078563.72650.61"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","unstructured":"Berry DA Mueller P Grieve AP Smith MK Parke T Krams M. 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